The present invention relates to a novel dipeptide compound which inhibits enzymatic activity of an HIV protease and to an anti-AIDS medicine which suppresses in vivo HIV growth utilizing the HIV protease inhibitory activity of the dipeptide compound.
Human immunodeficiency viruses (HIV) which induce AIDS produce a Gag protein, reverse transcriptase, or the like used for formation of the viruses as a precursor protein in host cells. The precursor proteins can function only when cut into a specific size using a protease (HIV protease) originating from viruses. An HIV protease inhibitor which inhibits the activity of the HIV protease and thereby blocks formation and maturation of infectious virus particles can be used as an anti-virus agent. Several such HIV protease inhibitors have already been reported.
One kind of such compounds is synthetic peptide-like compounds called a substrate transition state mimetic (T. Robins et al., J. Acquire. Immun. Defic. Syndr., 6, 162, 1993, etc.). The compounds which have been reported to be useful as an HIV protease inhibitor include a hydroxyethyl amine derivative such as Ro31-8959 which contains a phenylalanine xcfx86 [CH(OH)CH2N] decahydroisoquinoline carboxylic acid skeleton similar to an amino acid sequence selectively cut by an HIV protease, -Tyr*Pro-, or -Phe*Pro-(N. A. Roberts, et al., Science, 248, 358-361, 1990), a hydroxymethylcarboxamide derivative such as a peptide containing a phenylalanine xcfx86 [CH(OH)CON] proline-like skeleton (T. F. Tam, et al., J. Med. Chem., 35, 1318-1320, 1992), and the like.
The inventors of the present invention have previously found that a synthetic peptide compound containing a 3-amino-2-hydroxy-4-phenylbutanoic acid in the skeleton structure strongly inhibits HIV protease activity and is useful as an anti-AIDS medicine. The inventors have proposed such a peptide as an HIV protease inhibitor (Japanese Patent Application Laid-open No. 10-025242, etc.).
However, when administering such an HIV protease inhibitor orally or parenterally, it is difficult to maintain its concentration in blood sufficiently high to suppress duplication of viruses in infected cells in the body. Quite a few HIV protease inhibitors therefore remain still in the clinical test stage. One reason for this is incapability of the medical component to reach inside the cells due to interaction with proteins (particularly xcex11-acidic glycoproteins) which are present in plasma (e.g. J. K. Lazdins, et al., The Journal of Infectious Diseases, 175, 1063-1070, 1997). In view of this situation, development of a compound exhibiting a strong anti-virus action which is less affected by plasma proteins has been desired.
The present invention has been achieved in view of the above situation and has an object of providing a novel dipeptide compound which can exhibit a strong action and can maintain a high concentration in cells in the presence of plasma proteins, as compared with conventional HIV protease inhibitors comprising a substrate transition state mimetic peptide compound heretofore proposed as an anti-AIDS medicine. Another object of the present invention is to provide an anti-AIDS medicine comprising the novel dipeptide compound as an effective component, which can achieve a curative effect at a small dose.
The present invention relates to novel dipeptide compounds represented by the following formula (I) or (II), or pharmaceutically acceptable salts thereof, 
wherein R1, R2, and R3 independently represent a linear or branched, saturated or unsaturated lower alkyl group, alkoxyl group, alkylamino group, or dialkylamino group having 1-4 carbon atoms (with a carbon atom being either replaced by an oxygen atom or not), a halogeno group, or a hydrogen atom, provided that all of the R1, R2, and R3 are not a hydrogen atom at the same, R2 and R3 may form a ring together; R4 represents a linear or branched lower alkyl group having 1-4 carbon atoms or a hydrogen atom; X is a methylene group or a sulfur atom; Y represents a five or six member monocyclic or polycyclic hydrocarbon group, a heterocyclic group having a structure in which one or more carbon atom in the monocyclic or polycyclic hydrocarbon group is replaced by a hetero atom, an aryloxyalkyl group having 12 or less carbon atoms, in which the aromatic ring may be substituted with an alkyl group, alkoxy group, halogeno group, amino group or hydroxyl group; and Z represents an aliphatic hydrocarbon group having 1-6 carbon atoms or an aromatic hydrocarbon group having 12 or less carbon atoms in which the aromatic ring may be substituted with an alkyl group, alkoxy group, or halogeno group, or one or more carbon atom in the aromatic hydrocarbon group may be replaced by a hetero atom.
The present invention preferably relates to a dipeptide compound of the above formula (I) or (II), in which Y is a group represented by the following formula (III) or (IV), and Z is a group represented by the following formula (V) or a linear or branched lower alkyl group having 6 or less carbon atoms, or a pharmaceutically acceptable salt thereof, 
wherein R5 represents a linear or branched lower alkyl group having 1-4 carbon atoms or a halogeno group, R6 represents an amino group or hydroxyl group, R7, R8, and R9 represent a hydrogen, a methyl group, or a fluoro group, R10-R14 individually represent a linear or branched lower alkyl or alkoxy group having 1-4 carbon atoms, a halogeno group, or a hydroxyl group,
R15-R19 individually represent a linear or branched lower alkyl or alkoxy group having 1-4 carbon atoms, a halogeno group, or a hydrogen atom, Q is an alkylene group, n is 0 or 1, and m is 0-6.
The present invention preferably relates to a novel dipeptide compound having a methyl group for R4 and a sulfur atom for X in the above formula (I) or (II), and to a pharmaceutically acceptable salt thereof.
The other preferable compounds of the present invention is a novel dipeptide compound having the group of the formula (III) for Y and the group of the formula (V) for Z in the above formula (I) or (II), and a pharmaceutically acceptable salt thereof. In this instance, preferably R5 is a methyl group or a chloro group, R6 is a hydroxyl group or amino group, and R7-R9 are a hydrogen, and more preferably R15 is a methyl group, R16-R18 is a hydrogen, and R19 is a methyl group or a hydrogen.
Furthermore, among the dipeptide compounds or pharmaceutically acceptable salts thereof, having the group of the formula (III) for Y, the group of the formula (V) for Z, a methyl group or chloro group for R5, a hydroxyl group or amino group for R6, a hydrogen for R7-R9, a methyl group for R15, a hydrogen for R16-R18, and a methyl group or hydrogen for R19 in the above formula (I) or (II), a compound having a hydrogen for R1, a linear or branched, saturated or unsaturated lower alkoxy group having 1-4 carbon atoms, in which the carbon atoms may be replaced by oxygen atoms, or a hydrogen for R2 or R3 (R2 and R3 must not be hydrogen at the same time), or having a ring formed by R2 and R3 in combination, is more preferable. A particularly preferable compound is that having a hydrogen for R1, a methoxy group, ethoxy group, or hydrogen for R2 or R3 (provided that R2 and R3 must not be hydrogen at the same time), or a methylenedioxy group as a ring formed by R2 and R3 in combination.
The present invention relates to an anti-AIDS medicine comprising one of these novel dipeptide compounds or a pharmaceutically acceptable salt thereof as an effective component.
The dipeptide compound of the present invention is a hydroxymethylcarboxamide derivative, which is an xcex1-aminocarboxamide containing a 3-amino-2-hydroxy-4-substituted-phenylbutanoyl skeleton and a five-membered ring connected via an amide bond, as a substrate transition state mimetic structure essential for HIV protease inhibition activity. In the dipeptide compound of the present invention, if the 3-amino-2-hydroxy-4-substituted-phenylbutanoyl skeleton is provided with a (2S, 3S) steric configuration and the xcex1-aminocarboxamide containing a five-membered ring has a steric configuration in which the corresponding xcex1-amino acid is an (L)-isomer, such a compound exhibits particularly high HIV protease inhibition activity.
As examples of the linear or branched, saturated or unsaturated lower alkyl group, alkoxyl group, alkyl amino group, or dialkyl amino group having 1-4 carbon atoms (with a carbon atom being either replaced by an oxygen atom or not), represented by R1, R2, and R3 in the above formula (I) or (II), the following groups can be given: methyl group, ethyl group, propyl group, butyl group, isopropyl group, sec-butyl group, tert-butyl group, vinyl group, allyl group, isopropenyl group, 1-propenyl group, methoxy group, ethoxy group, propoxy group, butoxy group, isopropoxy group, sec-butoxy group, tert-butoxy group, vinyloxy group, allyloxy group, isopropenyloxy group, 1-propenyloxy group, methoxymethoxy group, ethoxymethoxy group, methoxyethoxy group, methylamino group, ethylamino group, propylamino group, dimethylamino group, and diethylamino group. As halogeno groups, fluoro group, chloro group, and bromo group can be given. As cyclic compound formed by R2 and R3, a methylenedioxy group, ethylenedioxy group, ethylene group, and the like can be given. Of these groups, lower alkoxy groups such as a methoxy group, ethoxy group, propoxy group, butoxy group, isopropoxy group, and methylenedioxy group are preferable, with particularly preferable groups being a methoxy group, ethoxy group, and methylenedioxy group.
As examples of the linear or branched lower alkyl group having 1-4 carbon atoms represented by R4 in the above formula (I) or (II), a methyl group, ethyl group, propyl group, butyl group, isopropyl group, and sec-butyl group can be given. A methyl group is particularly preferable group.
X in the above formula (I) or (II) is a methylene group or a sulfur atom. The sulfur atom may be present as a thio group, sulfinyl group, or sulfonyl group.
As the xcex1-amino acid residue consisting of the five-membered ring containing the groups represented by X and R4, proline, 3,3-dimethylpyrrolidine-2-carboxylic acid, 1,3-thiazolidine-4-carboxylic acid, 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid, and the like can be given, with 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid being particularly preferable.
As examples of the five-membered or six-membered monocyclic hydrocarbon group, polycyclic hydrocarbon group, or heterocyclic group derived from the monocyclic or polycyclic hydrocarbon group by replacing one or more carbon atom with a hetero atom, represented by Y in the above formula (I) or (II), the following groups can be given: phenyl group, 1-naphthyl group, 2-naphthyl group, phenylphenyl group, methylphenyl group, dimethylphenyl group, trimethylphenyl group, ethylphenyl group, methylethylphenyl group, diethylphenyl group, triethylphenyl group, propylphenyl group, dipropylphenyl group, butylphenyl group, pentylphenyl group, hexylphenyl group, cyclohexylphenyl group, fluorophenyl group, chlorophenyl group, bromophenyl group, difluorophenyl group, dichlorophenyl group, dibromophenyl group, chlorofluorophenyl group, trifluorophenyl group, trichlorophenyl group, fluoromethylphenyl group, trifluoromethylphenyl group, tetrahydrofuranyl group, tetrahydropyranyl group, furfuryl group, benzofurfuryl group, thienyl group, benzothienyl group, pyrrolyl group, imidazoyl group, pyridyl group, pyrimidyl group, pyridazyl group, pyrazyl group, tetrazinyl group, quinolyl group, isoquinolyl group, and pyridyl methyl group.
The following can be given as examples of the aryloxyalkyl group having 12 or less carbon atoms, in which the aromatic ring may be substituted with an alkyl group, alkoxy group, or halogeno group:phenoxymethyl group, methylphenoxy methyl group, dimethylphenoxymethyl group, trimethylphenoxymethyl group, ethylphenoxymethyl group, diethylphenoxymethyl group, triethylphenoxymethyl group, chlorophenoxymethyl group, dichlorophenoxymethyl group, trichlorophenoxymethyl group, fluorophenoxymethyl group, difluorophenoxymethyl group, trifluorophenoxymethyl group, trifluoromethylphenoxymethyl group, methoxyphenoxymethyl group, dimethoxyphenoxymethyl group, and trimethoxyphenoxymethyl group.
The compound in which Y is the group represented by the formula (III) or (IV) is preferable; provided that in the formula (III), R5 indicates a linear or branched lower alkyl group having 1-4 carbon atoms or a halogeno group, R6 is an amino group or hydroxyl group, and R7, R8 and R9 individually represent a hydrogen, methyl group, or fluoro group, and in the formula (IV), R10-R14 individually represent a linear or branched lower alkyl or alkoxy group having 1-4 carbon atoms, halogeno group, amino group, hydroxyl group, or hydrogen.
As examples of the linear or branched lower alkyl group having 1-4 carbon atoms, or the halogeno group represented by R5 in the formula (III), a methyl group, ethyl group, propyl group, butyl group, isopropyl group, sec-butyl group, fluoro group, chloro group, and bromo group can be given. Of these, methyl group, ethyl group, choro group, and bromo group are preferable, with methyl group and choro group being particularly preferable.
R7, R8, and R9 in the formula (III) individually represent a hydrogen, a methyl group, or a fluoro group, with hydrogen or fluoro group being particularly preferable.
As specific examples of the group Y in the formula (III), of which preferable substituents are selected from the groups given for R5 to R9, 3-hydroxy-2-methylphenyl group, 2-ethyl-3-hydroxyphenyl group, 3-amino-2-methylphenyl group, 3-amino-2-ethylphenyl group, 3-amino-2-chlorophenyl group, and 2-chloro-3-hydroxyphenyl group, with 3-hydroxy-2-methylphenyl group, 3-amino-2-methylphenyl group, 3-amino-2-chlorophenyl group, and 2-chloro-3-hydroxyphenyl group being particularly preferable.
As examples of the linear or branched lower alkyl or alkoxyl group having 1-4 carbon atoms, halogeno group, or hydrogen represented by R10-R14 in the formula (IV), a methyl group, ethyl group, propyl group, butyl group, isopropyl group, sec-butyl group, fluoro group, chloro group, bromo group, methoxy group, ethoxy group, propoxy group, butoxy group, isopropoxy group, sec-butoxy group, tert-butoxy group, and hydrogen can be given. Of these, methyl group, fluoro group, choro group, and hydrogen are preferable. Particularly preferable selection is a methyl group for R10 and R14 and hydrogen atom for R11-R13, or a methyl group for R10, R12, and R14 and hydrogen for R11 and R13.
Examples of the aliphatic hydrocarbon group having 1-6 carbon atoms or aromatic hydrocarbon group having 12 or less carbon atoms in which the aromatic ring may be substituted with an alkyl group, alkoxy group, or halogeno group or one or more carbon atoms in the aromatic hydrocarbon group may be replaced by hetero atoms include:phenyl group, 1-naphthyl group, 2-naphthyl group, phenylphenyl group, methylphenyl group, dimethylphenyl group, trimethylphenyl group, ethylphenyl group, methylethylphenyl group, diethylphenyl group, propylphenyl group, dipropylphenyl group, butylphenyl group, pentylphenyl group, hexylphenyl group, cyclopentylphenyl group, cyclohexylphenyl group, fluorophenyl group, chlorophenyl group, bromophenyl group, difluorophenyl group, dichlorophenyl group, dibromophenyl group, chlorofluorophenyl group, trifluorophenyl group, trichlorophenyl group, fluoromethylphenyl group, trifluoromethylphenyl group, benzyl group, 1-phenethyl group, 2-phenethyl group, phenylpropyl group, phenylbutyl group, phenylpentyl group, phenylhexyl group, methylbenzyl group, 1-methylphenethyl group, dimethylbenzyl group, dimethylphenethyl group, trimethylbenzyl group, ethylbenzyl group, diethylbenzyl group, chlorobenzyl group, dichlorobenzyl group, fluorobenzyl group, difluorobenzyl group, trifluorobenzyl group, chloromethylbenzyl group, fluoromethylbenzyl group, methoxybenzyl group, dimethoxybenzyl group, ethoxybenzyl group, diethoxybenzyl group, piperonylbenzyl group, 1-indanyl group, and 2-indanyl group.
As the aliphatic hydrocarbon groups having 1-6 carbon atoms, a methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, hexyl group, and the like are preferable. Excellent results can be expected when a branched alkyl group having 3-5 carbon atoms such as a tert-butyl group is selected.
Given as preferable examples of the aromatic hydrocarbon group having 12 or less carbon atoms in which the aromatic ring may be substituted with an alkyl group, alkoxy group, or halogeno group, or one or more carbon atoms in the aromatic hydrocarbon group may be replaced by hetero atoms, represented by Z in the formula (I) or (II) are compounds shown by the formula (V), wherein R15-R19 individually represent a linear or branched lower alkyl or alkoxy group having 1-4 carbon atoms, a halogeno group, or a hydrogen atom. Specific examples of the linear or branched lower alkyl or alkoxy group having 1-4 carbon atoms or the halogeno group represented by R15-R19 in the formula (V) include: methyl group, ethyl group, propyl group, butyl group, isopropyl group, sec-butyl group, methoxy group, ethoxy group, propoxy group, butoxy group, isopropoxy group, sec-butoxy group, tert-butoxy group, fluoro group, chloro group, and bromo group. More preferable selection is a methyl or chloro group for R15, a hydrogen, methyl, or fluoro group for R16-R19, and particularly a methyl group for R15 and a hydrogen or fluoro group for R16-R18, or a methyl group for R15 and R19 and a hydrogen or fluoro group for R16-R18.
Specific examples of particularly preferable compounds of the present invention include, but are not limited to the following compounds: (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(3-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(3-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-ethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-ethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-ethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-ethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3,4-methylenedioxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(3,4-methylenedioxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3,4-methylenedioxyphenyl) -butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(3,4-methylenedioxyphenyl) -butanoyl]-5,5-Dimethyl-1-3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-propoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-propoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-propoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-propoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-isopropoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-isopropoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-isopropoxyphenyl) butanoyl]-5-,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-isopropoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3,4-dimethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(3,4-dimethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3,4-dimethoxyphenyl) -butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3,5-dimethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(3,5-dimethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3,4-dimethoxyphenyl) -butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3,4,5-trimethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(3,4,5-trimethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3,4,5-trimethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-chlorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-chlorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-chlorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3-chlorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(3-chlorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3-chlorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-fluorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-fluorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-fluorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3-fluorophenyl)butanoyl]-5,5-dimethyl-1-3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(3-fluorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3-fluorophenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-methylphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-methylphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-methylphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(5-fluoro-2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(4-fluoro-3-hydroxy-2-methylbenzoyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(4-fluoro-3-hydroxy-2-methylbenzyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(5-fluoro-2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-ethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-ethoxyphenyl)butancyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(4-ethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(3,4-methylenedioxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(3,4-methylenedioxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(3,4-methylenedioxyphenyl) -butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-propoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-propoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(4-propoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methylbenzoyl)amino-4-(4-isopropoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-chlorobenzoyl)amino-4-(4-isopropoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(tert-butyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(4-isopropoxyphenyl) -butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-methylbenzoyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-methylbenzoyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-methylbenzoyl)amino-4-(4-ethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-methylbenzoyl)amino-4-(4-ethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-methylbenzoyl)amino-4-(4-isopropoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-methylbenzoyl)amino-4-(4-isopropoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-methylbenzoyl)amino-4-(3,4-methylenedioxyphenyl)butanoyl]5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl-3-[(2S,3S)-2-hydroxy-3-(3-amino-2-methylbenzoyl)amino-4-(3,4-methylenedioxyphenyl) -butanoyl]-5,5-Dimethyl-1-3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(4-methoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(4-ethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(4-ethoxyphenyl)butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(4-isopropoxyphenyl) -butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(4-isopropoxyphenyl) -butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2-methylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(3,4-methylenedioxyphenyl) -butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R)-N-(2,6-dimethylbenzyl)-3-[(2S,3S)-2-hydroxy-3-(2,6-dimethylphenoxyacetyl)amino-4-(3,4-methylenedioxyphenyl) -butanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide.
Specific examples of the pharmaceutically acceptable salt of dipeptide compound of the present invention include a hydrochloride, acetate, methanesulfonate, oxalate, citrate, and succinate.
The dipeptide compounds shown by the above formula (I) or (II) can be easily prepared using a known method of synthesizing xcex1-hydroxy-xcex2-amino acid (R. Nishizawa, et al., J. Med. Chem., 20, 510-515, 1977; W. Yuan et al., J. Med. Chem., 36, 211-220, 1993; Matsumoto et al., Japanese Patent Application Laid-open No. 10-59909; or Suzuki et al., Japanese Patent Application Laid-open No. 9-157247), and a known method of synthesizing a hydroxymethylcarboxamide-type HIV protease inhibitor (T. Mimoto et al. J. Med. Chem., 42, 1789-1802, 1999, etc.).
For example, an aminoaldehyde derivative (in which the amino group is protected) is prepared by a conventional method and reacted with hydrogen cyanide or its equivalent to produce a cyanhydrin derivative, which is hydrolyzed under acidic conditions, for example, in the presence of hydrochloric acid, thereby obtaining the target xcex1-hydroxy-xcex2-amino acid. Alternatively the xcex1-hydroxy-xcex2-amino acid can be prepared by hydrolyzing xcex1-amino-xcex2xe2x80x2, xcex1xe2x80x2-dihaloketone derivatives, prepared by a conventional method, in the presence of a base. In this instance, the product which is predominantly obtained is a more preferable steric isomer (2S,3S). The resultant xcex1-hydroxy-xcex2-amino acids can be converted into amino-protected xcex1-hydroxy-xcex2-amino acid derivatives by the reaction with a commonly used amino group protecting reagent such as Boc2O or Z-Cl in the presence of an organic base such as triethylamine or a mineral base such as sodium hydroxide. Thus obtained amino-protected xcex1-hydroxy-xcex2-amino acids can be recrystallized or formed to ester-derivative and then separated using column chromatography, thereby obtaining the derivative containing only (2S, 3S) derivative which is more preferable.
On the other hand, the hydroxymethylcarboxamide compound can be synthesized, for example, by following procedure.
An xcex1-aminocarboxamide derivative, which has a substituted benzyl group on the nitrogen atom of its carbamoyl group, is condensed with an amino-protected (2S,3S)-3-amino-2-hydroxy-4-substituted-phenylbutanoic acid using a carbodiimide reagent (e.g DCC (N,Nxe2x80x2-dicyclohexylcarbodiimide), EDC (1-ethyl-3-(3-N,Nxe2x80x2-dimethylaminopropyl)carbodiimide), etc.) in the presence of additives (HOBt (N-hydroxybenzotriazole), HOSu (N-hydroxysuccinimide), and the like), then deprotecting the amino group by using an acid such as hydrochloric acid or by catalytic hydrogenation using a Pd catalyst. The dipeptide of present invention is obtained by reacting the resulting dipeptide amine derivative with a desired amino-modified carboxylic group activated by the acid chloride method, the mixed anhydride method (diphenyl phosphoryl chloride, and the like), or the above-mentioned carbodiimide method.
The target compound may also be synthesized by following process.
First synthesize a dipeptide derivative protected with an appropriate protecting group such as an acetyl group on the hydroxyl group or amino group of R5 in the above formula (I) or (II). Then deprotect using an acid or alkali.
As required, impurities are removed by a suitable means such as column chromatography, recrystallization, and the like, and resulting purified compound can be used as an HIV protease inhibitor. The structure of dipeptide compound of the present invention can be easily determined by the NMR method, spectrophotometric method such as IR absorption, or mass spectrometry, with reference to the structure originating from raw material compounds.
The dipeptide compound of the present invention exhibits high HIV protease inhibitory activity. Because of this characteristics, the compound can become the compound which exhibits anti-virus activity by blocking formation and maturation of infective viral particles in HIV T-lymphocytes. Therefore, the compound is useful in phamaceutical application as an anti-AIDS agent due to this effect of blocking formation and maturation of infective viral particles.
When applying the dipeptide compound of the present invention to clinical application as an anti-AIDS medicine, the compound may be administered as compounding of medicine prepared according to a conventional method by using conventional pharmaceutical substances and vehicles. Specifically, the compound may be non-orally administered as intravenous or intramuscular injection, spray, or suppository, or orally administered as granules, capsules, fluid, tablets. Because the dipeptide compound of the present invention is a low molecular compound with excellent in vivo stability and superior gastrointestinal absorption, oral administration as granules, capsules, fluid, tablets, or the like is appropriate for the compound. Although a dose is determined according to symptoms of the patients, the therapeutic objective such as suppression of AIDS symptom, control of AIDS progress, the age and sex of the patients, and the like, an approximate range is between 10 mg and 2 g per dose for adults who are administered 1-4 times a day.